It appears that there is a conformation change in the C4 domain of HIV gp120 that allows gp120 to evade a neutralizing immune response and which may contribute to the toxicity of gp120. We synthesized peptides from the C4 domain of gp120 in 2 forms; helical and cyclic. We learned that both forms, although having the same amino acid sequence and ability to bind recombinant soluble CD4, have very different immunological properties. When the C4 peptomer having an alpha helical conformation is used as the immunogen in monkeys, antibodies are formed that react with the parent gp120 and the antibodies block gp120 binding to CD4 but they do not inhibit HIV infection in vitro. Monkeys that were immunized with the peptomer had a very pronounced T helper cell response but, surprisingly, showed increased viremia following intrarectal challenge with live SIV. It thus appears that in monkeys C4 is contributing to SIV disease progression. 9 out of 10 human sera that were HIV+ contain antibodies that react with the C4 peptomer in the helical conformation but 3 out of 10 had antibodies that reacted with C4 in the cyclic conformation. In addition, this year we learned that, when the cyclic C4 peptide is used as an immunogen in rabbits, antibodies are formed that react with the parent gp120 but they do not block gp120 binding to CD4. In addition, these antibodies magnify the toxic effects of gp120 on T cell production of IL-2, probably by crosslinking CD4 on the T cell surface. Affinity purified human anti cyclic C4 antibodies also augmented IL-2 attenuation by gp120. In summary, natural HIV infection causes the production of antibodies against the linear, helical and/or cyclic C4 peptide but, the antibodies appear to be harmful to the HIV+ host. Thus, even though the C4 domain of gp120 is highly conserved, it contributes to HIV pathogenesis by avoiding neutralizing immune responses The end result represents another way HIV protects itself from destruction by the immune system. The work clearly signals immune responses against C4 as being harmful and studies of future vaccine formulations should carefully focus in part on the harmful roles played by C4 if the C4 domain is a component of the vaccine.